The selective non-peptidic delta opioid agonist SNC80 does not facilitate intracranial self-stimulation in rats

Abstract

Delta opioid receptor agonists are under development for a variety of clinical applications, and some findings in rats raise the possibility that agents with this mechanism have abuse liability. The present study assessed the effects of the non-peptidic delta opioid agonist SNC80 in an assay of intracranial self-stimulation (ICSS) in rats. ICSS was examined at multiple stimulation frequencies to permit generation of frequency-response rate curves and evaluation of curve shifts produced by experimental manipulations. Drug-induced leftward shifts in ICSS frequency-rate curves are often interpreted as evidence of abuse liability. However, SNC80 (1.0-10 mg/kg s.c.; 10-56 mg/kg i.p.) failed to alter ICSS frequency-rate curves at doses up to those that produced convulsions in the present study or other effects (e.g. antidepressant effects) in previous studies. For comparison, the monoamine releaser d-amphetamine (0.1-1.0 mg/kg, i.p.) and the kappa agonist U69,593 (0.1-0.56 mg/kg, i.p.) produced dose-dependent leftward and rightward shifts, respectively, in ICSS frequency-rate curves, confirming the sensitivity of the procedure to drug effects. ICSS frequency-rate curves were also shifted by two non-pharmacological manipulations (reductions in stimulus intensity and increases in response requirement). Thus, SNC80 failed to facilitate or attenuate ICSS-maintained responding under conditions in which other pharmacological and non-pharmacological manipulations were effective. These results suggest that non-peptidic delta opioid receptor agonists have negligible abuse-related effects in rats.

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

“…These blunted Max Rates normalized during the remaining passes. Decreased Max Rates can be the result of decreased hedonic value of stimulation (Do Carmo et al, 2009) or reduced performance ability (Carlezon and Chartoff, 2007). The time-course of these effects are consistent with our previous findings using central (Bechtholt-Gompf et al, 2010) or intra-cortical infusions of DHK (John et al, 2012).…”

“…We extend the previous literature by showing that blockade of astrocytic glutamate reuptake specifically in the CEA can induce anhedonia. The present findings also suggest that intra-CEA DHK has profound effects on maximum response rates in the ICSS paradigm, which can be indicative of decreased motivation or an anhedonic-like effect (Bechtholt-Gompf et al, 2010), as either decreasing the intensity of the stimulation or increasing the response requirement decreases maximum response rates (Do Carmo et al, 2009). Previous reports have shown that increased glutamate levels in the amygdala can induce other signs of depression such as social avoidance and disrupted circadian rhythms in rats (Lee et al, 2007).…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Kappa and Delta Opioids. Selective kappa opioid receptor agonists such as U50,488 (5,6-dimethoxy-N, N-dipropyl-2,3-dihydro-1H-inden-2-amine), U69,593 [Nmethyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide], and salvinorin A produce a dose-dependent depression of ICSS (Todtenkopf et al, 2004;Carlezon et al, 2006;Dinieri et al, 2009;Do Carmo et al, 2009;Negus et al, 2010Negus et al, , 2012aRussell et al, 2013). For example, Fig.…”

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

“…After initial shaping of lever press responding, rats were trained under a continuous reinforcement schedule of brain stimulation by using procedures similar to those described previously (Carlezon and Chartoff, 2007;Do Carmo et al, 2009;Negus et al, 2010a). During sessions lasting 30 to 60 min, each lever press resulted in the delivery of a 0.5-s train of square wave cathodal pulses (0.1-ms pulse duration), and stimulation was accompanied by illumination of the stimulus lights over the lever.…”